Myoclonus Secondary to Amantadine: Case Report and Literature Review

The usual adverse events of amantadine are dizziness, dry mouth, and peripheral edema. Postmarketing experience has revealed abnormal movements such as tremors, involuntary muscle contractions, and gait abnormalities. Herein, we report a case of an elderly male who presented with generalized twitching associated with amantadine. A 64-year-old male presenting with jerking movements within one day of onset was admitted. Sudden and involuntary distal lower and upper limb muscle twitching was observed. The subject presented subsequent brief movements when attempting to stand or hold arms antigravity. He was diagnosed with Parkinson’s disease three years ago. Eight days before the presentation to the emergency department, he consulted with his primary care physician, who prescribed amantadine to improve his motor symptoms. On the seventh day, he developed brisk abnormal movements. Laboratory exams, neuroimaging, and electroencephalogram were unremarkable. Amantadine was discontinued. After three days, the patient reported that his jerking movements had fully recovered. To the authors’ knowledge, 22 individuals with amantadine-associated myoclonus had already been reported in the literature. The pathophysiology of amantadine-induced myoclonus is probably related to serotoninergic pathways. Myoclonus secondary to amantadine was slightly more common in men. The population affected was elderly, with a mean and median age of 67.7 and 64 years.


Introduction
Amantadine hydrochloride was developed as an antiviral medication. One of the pioneer amantadine clinical trials showed improvement in the influenza virus infection course and motor symptoms of patients affected by Parkinson's disease. In 1973, the Food and Drug Administration approved amantadine for treating Parkinson's disease [1].
Herein, we present a case of an elderly male who presented with generalized twitching movements, probably secondary to amantadine. Moreover, we provide a table with all the reported cases and present a figure describing the therapeutic range based on amantadine reports and clinical trials.

Case Report
A 64-year-old male presenting with jerking movements within one day of onset was admitted to our emergency department. He reported that the abnormal involuntary movements became worse throughout the last day. His vital signs, such as temperature, heart rate, respiratory rate, and blood pressure, were within normal limits.
On neurological examination, sudden and involuntary distal lower and upper limb muscle twitching was observed. Additionally, the subject presented subsequent brief movements when attempting to stand or hold arms against gravity. Bradykinesia, tremor, and postural instability associated with shuffling gait were noted. The muscle mass and strength were normal (Grade 5-Medical Research Council). The assessment of cranial nerves was unremarkable. Deep tendon reflexes were normal and active. His neurological family history was unremarkable. Additionally, he had no history of known drug allergies or adverse drug reactions.
He was diagnosed with Parkinson's (Hoehn and Yahr stage II) three years ago. In the last month, the individual reported having more common off-periods with difficulty walking. He only used 100 mg levodopa + 25 mg benserazide tablet thrice daily. Eight days before the presentation to the emergency department, he consulted with his primary care physician, who added amantadine to improve his motor symptoms. Amantadine hydrochloride 100 mg tablet once a day for three days was started. After three days, he increased the amantadine dosage to one tablet twice daily. On the seventh day, he began with brisk abnormal movements.
Laboratory exams were within normal limits, including serum creatinine levels. A cranial computed tomography scan was normal. A brain magnetic resonance (1.5 Tesla) was normal without changes after contrast material. Cerebrospinal fluid analysis showed 60 mg/dL of glucose (98 mg/dL plasma glucose), 30 mg/dL protein, 0 leukocytes, and 0 red blood cells. An electroencephalogram was normal without background seizure activity, slowing, or suppressions.
On the second admission day, it was observed that the symptoms worsened approximately two hours after the amantadine administration (Video S1). It was hypothesized that his myoclonus was probably associated with amantadine. Clonazepam and hydration were started. Amantadine was discontinued. After three days, the patient reported that his jerking movements had fully recovered. In the long-term follow-up of one year, the patient did not have a recurrence of the myoclonus. He continued with his baseline Parkinson's symptoms and was administered 100 mg levodopa + 25 mg benserazide, one tablet, five times daily.

Discussion
The exact mechanism of amantadine for managing parkinsonism and drug-induced extrapyramidal reactions is unknown. However, five main indirect pathways have been studied to explain amantadine's involvement in the cortico-striato-pallido-thalamo-cortical loop ( Figure 1).
Amantadine is believed to activate presynaptic dopamine receptor D2 reducing the dopamine transporter related to dopamine reuptake [19]. In animal studies, amantadine inhibited monoamine oxidase B, decreasing dopamine degradation [20]. Interestingly, amantadine is an agonist of the σ1 receptors, which is probably related to the psychostimulant-like effects of this compound [21]. Amantadine blocks alpha-7 nicotinic receptors, which explains its anticholinergic side effects like xerostomia, urinary retention, and constipation [22].
The most common MCL presentation was multifocal jerks in the limbs, but focal jerks were also observed. In this context, some cases that described cranial myoclonus, also known as branchial or vocal myoclonus, involving facial muscles were misdiagnosed as stuttering [4,10]. Notably, amantadine is a type of NMDA antagonist, like ketamine and phencyclidine, which are well known to cause a head-twitch response in rat models [28]. Therefore, the association of myoclonus with amantadine therapy is expected. Notably, amantadine was prescribed for many different types of disorder (e.g., Parkinson's disease, progressive supranuclear palsy, disorders of consciousness, and depression), so differences from a pathophysiological point of view on the role of amantadine in these very different conditions is possible.
Amantadine-induced myoclonus was slightly more common in men (12/23). The population affected was the elderly, with a mean and median age of 67.7 (SD: 9.8) and 64 years (age range: 53-87). It is worth mentioning that the studied population involved patients with Parkinson's disease, which can explain the age of the people affected [29].
Most of the cases were not reported by movement disorder specialists, which could have led to possible misdiagnosis of the abnormal movement in some reports. In only 43% (10/23) of the cases, electrodiagnostic studies were performed. The description of supporting studies is essential for defining myoclonus sources [30]. The most frequent source of myoclonus was cortical, but some authors reported a subcortical origin.  In pharmacokinetic studies, the plasma concentration of amantadine ranged from 100 to 2000 ng/mL [31]. In elderly individuals, 1000 to 2000 ng/mL is considered dangerous by some authors due to a higher incidence of side effects such as hallucinations and delirium [31,32]. We reviewed the literature and provide a figure about the amantadine concentration ( Figure 2) [5,6,9,11,16,33,34]. Interestingly, all the cases that reported myoclonus had amantadine concentrations above 3000 ng/mL [9]. Despite prevailing renal elimination, the metabolism of amantadine is not yet fully clarified because 5-15% of an oral dose is apparently acetylated and acetylator phenotype might influence toxicity [35]. years (age range: 53-87). It is worth mentioning that the studied population involved patients with Parkinson's disease, which can explain the age of the people affected [29].
Most of the cases were not reported by movement disorder specialists, which could have led to possible misdiagnosis of the abnormal movement in some reports. In only 43% (10/23) of the cases, electrodiagnostic studies were performed. The description of supporting studies is essential for defining myoclonus sources [30]. The most frequent source of myoclonus was cortical, but some authors reported a subcortical origin.
The availability and costs regarding the measurement of serum amantadine levels are still a limitation to a specific approach to the adverse events associated with this medication. In this context, developing extended-release formulations with late peak plasma concentration and a longer half-life may be associated with increased side effects. Thus, assessing drug levels for adequately managing parkinsonism will be mandatory. Meanwhile, clinicians should rely on the Cockcroft-Gault formula to estimate creatinine clear- Figure 2. Plasma concentration of amantadine (ng/mL). Ineffective, effective, unknown, and toxic ranges [5,6,9,11,16,33,34].
The availability and costs regarding the measurement of serum amantadine levels are still a limitation to a specific approach to the adverse events associated with this medication. In this context, developing extended-release formulations with late peak plasma concentration and a longer half-life may be associated with increased side effects. Thus, assessing drug levels for adequately managing parkinsonism will be mandatory. Meanwhile, clinicians should rely on the Cockcroft-Gault formula to estimate creatinine clearance as a risk factor for developing side effects related to amantadine. Noteworthy, levodopa, considered the mainstay of treating Parkinson's disease, was already associated with myoclonus. However, levodopa-induced myoclonus is a relatively late complaint because most individuals only present this side effect after ten years of levodopa use [36].
Eighty to ninety percent of amantadine is excreted unchanged by glomerular filtration and tubular secretion. In this way, renal dysfunction can cause accumulation of this drug in several organs, such as the lungs and kidneys. Interestingly, the approximate half-life of amantadine is sixteen hours in individuals with normal renal function and eight days in dialytic individuals [31]. Therefore, we analyzed the data of the cases regarding renal impairment in the individuals reported in Table 1. Of the 23 subjects, 12 had at least mildly decreased renal function. However, some authors did not describe creatinine levels or creatinine clearance.
Dames et al. reported a case of a patient falling several times a day for years. The authors reported a possible association between falling and amantadine therapy. In this context, they observed that the patient had generalized myoclonus contributing to his imbalance. The amantadine clinical trials revealed an increased dose-dependent percentage of falls in patients with Parkinson's disease [37,38]. GOCOVRI's trials for levodopa-induced dyskinesia demonstrated a higher incidence of falls with amantadine. This finding was mainly observed in patients over 65 years old [39].

Conclusions
Myoclonus secondary to amantadine has rarely been reported in the literature. The pathophysiology of this association is probably related to serotoninergic pathways. Clinicians should consider amantadine-induced myoclonus as a cause of falling in Parkinson's disease patients. Future reports should describe electrodiagnostic studies for a determination of the myoclonus source.
Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/clinpract13040075/s1, Video S1: Asterixis, Table S1: FreeText and MeSH search terms in the US National Library of Medicine. Informed Consent Statement: Written informed consent has been obtained from the patient to publish this paper. Data Availability Statement: Not applicable.

Conflicts of Interest:
The authors declare no conflict of interest.